Mammographic density (MD) is a well-established and strong risk factor for first primary breast cancer. Women with invasive cancer in one breast are at 2-5 times higher risk of developing a contralateral breast cancer (CBC) compared to the general population risk of a first primary breast cancer. We and other researchers have shown that the treatment a woman receives for her first primary can alter her risk of developing CBC. Studies show MD is altered in response to some hormonal and other treatments, increasing with menopausal estrogen and progesterone therapy, and decreasing with tamoxifen, an anti-hormonal treatment as well as chemotherapy. It is plausible that MD, both before and after treatment, may be useful clinical markers of risk of CBC in women with a first primary breast cancer. As a result of improved screening and treatment, there are increasing numbers of survivors of breast cancer. However, there are few known clinical determinants of subsequent CBC, limiting women and health care providers in the assessment and management of this risk. The ongoing Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) II Study is a population-based study of 800 CBC cases and 800 unilateral breast cancer (UBC) controls currently being recruited and interviewed, along with having their breast cancer diagnosis and treatment medical records reviewed. We now propose to: retrieve mammograms taken at, or within a year prior to, the first breast cancer diagnosis and those at 12-18 months following diagnosis; digitize film mammograms; and quantitatively assess MD using both the well-established standard thresholding method (Cumulus) and a novel automated density measure (Variation or V). Our Primary Specific Aims are: 1. To estimate the relationship between MD (both %MD and absolute dense area, using the Cumulus thresholding program) of the contralateral breast around the time of the first diagnosis (at or up to one year prior) and the rik of a subsequent diagnosis of CBC invasive breast cancer in the contralateral breast; 2. To estimate the relationship between MD (both %MD and dense area, using Cumulus) of the contralateral breast at 12-18 months following initial diagnosis (when initial chemotherapy and radiation treatments are likely completed) and the risk of a subsequent diagnosis of invasive breast cancer in the contralateral breast; and 3. To assess changes in MD of the contralateral breast before and after treatment (and/or after initiation of hormonal treatment) by treatment modality. Our Secondary Specific Aims are: 1. To estimate whether change in MD (%MD or dense area) of the contralateral breast before and after treatment is associated with risk of a subsequent diagnosis of invasive breast cancer in the contralateral breast; 2.To address the above Aims using V, an automated, validated, breast density measurement and compare results with those derived from the Cumulus measure. The novel study we propose could be useful for identifying women at high risk of CBC and it addresses an understudied issue that is of high clinical importance to the many women who survive their first primary breast cancer. PUBLIC HEALTH RELEVANCE: Women with a first primary invasive breast cancer are at high risk of developing a second primary breast cancer in the contralateral breast (CBC). Mammographic density (MD) is a well-established and strong modifiable risk factor for first primary breast cancer. This study aims to determine whether MD can be used as a marker of risk of CBC, thus providing new opportunities to influence clinical management and improve outcomes. We propose a novel study that is of high clinical importance to the many women who survive their first primary breast cancer.